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Planar cell polarity in kidney development and disease

Brzoska, HL; (2017) Planar cell polarity in kidney development and disease. Doctoral thesis , UCL (University College London).

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Abstract

Planar cell polarity (PCP) is a signalling pathway regulating epithelial cell alignment and coordinated organisation, processes that are essential for the development and maintenance of healthy organs and tissues. In this thesis, I hypothesised that the core PCP protein, Celsr1 is essential for normal kidney development. Furthermore, I predicted that PCP proteins would be disrupted in a model of renal disease induced by folic acid. Kidneys of mice homozygous for a mutation in Celsr1 (Celsr1Crsh/Crsh) were significantly smaller compared with wild-type littermates and contained a reduced number of ureteric bud tips as assessed by optical projection tomography at embryonic day (E)13.5. The size of the bud tips and the angle at which they branched were unchanged. At E17.5, orientation of mitotic chromosomes was significantly disrupted in Celsr1Crsh/Crsh mutants compared with wild-type embryos. There was an occasional dilatation of proximal tubules and Bowman’s capsules surrounding the glomeruli, but not an overtly-cystic phenotype. I also examined whether Celsr1 interacted with another PCP component, Vangl2 in kidney development. I found that E13.5 Celsr1Crsh/+:Vangl2Lp/+ double heterozygous kidneys were also smaller compared with wild type littermates and had a significantly reduced UB tip number. At E17.5, a loss of corticomedullary differentiation with very few fully developed glomeruli and a disrupted mitotic orientation were observed in Celsr1Crsh/+:Vangl2Lp/+ kidneys compared with wild type littermates. During kidney injury induced by folic acid, a reduction in levels of Celsr1, normally expressed on the apical surface of proximal tubules, was seen in both the acute and fibrotic phases of this model. This data highlights that Celsr1 and the interaction between Celsr1 and Vangl2 are critical for normal kidney development and PCP proteins have a potential role in the progression of renal disease.

Type: Thesis (Doctoral)
Title: Planar cell polarity in kidney development and disease
Event: UCL (University College London)
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1558749
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